title: Clonal expansions and short telomeres are associated with neoplasia in early-onset, but not late-onset, ulcerative colitis.
abstract: BACKGROUND
  Patients with ulcerative colitis (UC) are at risk of developing colorectal cancer. We have previously reported that cancer progression is associated with the presence of clonal expansions and shorter telomeres in nondysplastic mucosa. We sought to validate these findings in an independent case-control study.
  
  
  METHODS
  This study included 33 patients with UC: 14 progressors (patients with high-grade dysplasia or cancer) and 19 nonprogressors. For each patient, a mean of 5 nondysplastic biopsies from proximal, mid, and distal colon were assessed for clonal expansions, as determined by clonal length altering mutations in polyguanine tracts, and telomere length, as measured by quantitative PCR. Both parameters were compared with individual clinicopathological characteristics.
  
  
  RESULTS
  Clonal expansions and shorter telomeres were more frequent in nondysplastic biopsies from UC progressors than nonprogressors, but only for patients with early-onset of UC (diagnosis at younger than 50 years of age). Late-onset progressor patients had very few or no clonal expansions and longer telomeres. A few nonprogressors exhibited clonal expansions, which were associated with older age and shorter telomeres. In progressors, clonal expansions were associated with proximity to dysplasia. The mean percentage of clonally expanded mutations distinguished early-onset progressors from nonprogressors with 100% sensitivity and 80% specificity.
  
  
  CONCLUSIONS
  Early-onset progressors develop cancer in a field of clonally expanded epithelium with shorter telomeres. The detection of these clones in a few random nondysplastic colon biopsies is a promising cancer biomarker in early-onset UC. Curiously, patients with late-onset UC seem to develop cancer without the involvement of such fields.
authors.affiliation: *Department of Pathology, †Department of Medicine, ‡Department of Biostatistics, and §Division of Gastroenterology, University of Washington, School of Medicine, Seattle, Washington; ‖Division of Anatomic Pathology, University of Utah, Salt Lake City, Utah; and ¶Division of Public Health Science, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Salk
authors.forename: Aasthaa
authors.initials: A
authors.lastname: Bansal
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lai
authors.forename: David A
authors.initials: DA
authors.lastname: Crispin
authors.forename: Cigdem H
authors.initials: CH
authors.lastname: Ussakli
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
authors.forename: Mary P
authors.initials: MP
authors.lastname: Bronner
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Brentnall
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Loeb
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Rosa Ana
authors.initials: RA
authors.lastname: Risques
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D002648:Child; D002999:Clone Cells / Q000473:pathology*; D003093:Colitis, Ulcerative / Q000150:complications* / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011068:Poly G / Q000235:genetics; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000209:etiology* / Q000473:pathology; D011379:Prognosis; D016615:Telomere / Q000235:genetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D011068:Poly G